Balloon for Use in Angioplasty with an Outer Layer of Nanofibers

ABSTRACT

An expandable balloon for use in angioplasty procedures comprises a balloon having an outer surface layer, the outer surface layer being made from electrospun nanofibers and incorporating at least one pharmaceutically active substance, such as nitric oxide (NO). The outer surface layer may be formed on a separate flexible tubular member or sock, which is slipped over the balloon. A method of treating cell disorders in tubular structures of a living being comprises the steps of placing a coated balloon at a treatment site within the tubular structures, expanding the balloon at the treatment site, and releasing the pharmaceutically active substance at the treatment site. Optionally, a stent may be crimped onto the balloon prior to insertion of the balloon and scent into the tubular structures of the living being.

TECHNICAL FIELD

The present invention relates to a balloon for use in angioplasty andits method of manufacture. The balloon may e.g. be suitable forinsertion into the vascular system of a living being, for example forexpanding an intravascular stent.

BACKGROUND OF THE INVENTION

Angioplasty balloons are often used in various diagnostic procedures andmedical treatments. For example, balloons are employed to expand stentsfor implantation in the lumen of a body duct for the treatment of bloodvessels exhibiting stenosis. Stents may contain drugs that afterimplantation elute to the surrounding tissue as to avoid side effectssuch as cell proliferation. Expandable stents are often placed on anangioplasty balloon catheter which, once in place, is inflated in orderto cause the stent to expand. Alternatively, stents may be made from amaterial which has a recovery capacity such as a super elastic alloy,such as Nitinol, so that the stents may automatically expand, once inplace. Such self expanding stents are often delivered by a telescopictube arrangement where an outer member is removed e.g. by forced slidingover an inner member to which the stent is fixed prior to expansion.

It is generally desired that medical devices for insertion into thevascular system of a living being meet certain physical requirements.For example, the surfaces of stents should be hydrophilic and have a lowsurface friction in order to facilitate introduction. The stent surfacesmay be coated with a pharmaceutical agent, such as nitric oxide (NO).Such nitric oxide releasing matrixes may also relax or prevent arterialspasm once the medical device is in place. Nitric oxide is further knownto inhibit the aggregation of platelets and to reduce smooth muscleproliferation, which is known to reduce restenosis. When delivereddirectly to a particular site, it has been shown to prevent or reduceinflammation at the site where medical personnel have introduced foreignobjects or devices into the patient.

International patent application WO 2004/006976 suggests a single layerof lipophilic bioactive material posited or applied to a balloon basematerial for a direct application to a vessel wall after the previousintroduction of another stent. According to the disclosure of thedocument, the balloon could be used for an angioplasty procedure withoutthe use of a stent. The layer of bioactive material can be posited onthe balloon by dipping, soaking or spraying.

Various nictric oxide (NO) donor compounds, pharmaceutical compositionscontaining such nitric oxide donor compounds and polymeric compositionscapable of releasing nitric oxide have also been proposed in the priorart. For example, European patent No. 1220694 B1 corresponding to U.S.Pat. No. 6,737,447 B1 discloses a medical device comprising at least onenanofiber of a linear poly(etihylenimine) diazeniumdiolate forming acoating layer on the device. This polymer is effective in deliveringnitric oxide to tissues surrounding medical device.

SUMMARY OF THE INVENTION

It is an object of preferred embodiments of the present invention toprovide a balloon which allows for improved drug delivery in the lumenof a body duct.

In a first aspect, the invention provides an expandable balloon for usein angioplasty procedures, comprising a balloon having an outer surfacelayer, the outer surface layer being made from nanofibers, such as spunnanofibers, such as electrospun nanofibers, and incorporating at leastone pharmaceutically active substance. In a second aspect, the inventionprovides a method of producing a balloon for use in angioplasty, themethod comprising the step of forming an outer surface layer for theballoon by nanofibers, such as by spinning of nanofibers, such as byelectrospinning of nanofibers, the outer surface layer containing atleast one pharmaceutically active substance. The body portion and theouter surface layer may, for example, define an expandable coatedangioplasty balloon, such as a PTA (percutaneous translumenalangioplasty) balloon, a PTCA (percutaneous translumenal coronarangioplasty) balloon or a PTNA (percutaneous translumenal neurovascularangioplasty catheter). Preferably, the outer surface layer is one whichconforms to the shape of the balloon, i.e. expands with the balloon whenthe balloon is inflated and contracts when the balloon is deflated. Theouter surface layer is preferably made from a polymer which will bedescribed in further detail below.

Typically, the diameter of the nanofibers is in the range of 2 to 4000nanometers, preferably 2 to 3000 nanometers, or less than 2000 or lessthan 1000 nanometers, such as less than 500 or less than 200 nanometers,less than 100 or less than 50 nanometers, such as less than 20 or lessthan 10 nanometers. Accordingly a large number of nanofibers is presenton the outer surface of the balloon. It will thus be appreciated thatthe nanofibers on the outer surface of the balloon define a largeaccumulated area, the area being larger with respect to the weight ofthe balloon than what is achievable with most other non-nanofiber ornon-spun surfaces. Accordingly, the surface constitutes a relativelylarge reservoir for the pharmaceutically active substance compared tothe weight of the coated balloon. Nanofibers may even be manufactured toa diameter of 0.5 nanometer which is close to the size of a singlemolecule.

It has been found that the production of nanofibers by e.g. spinning inmany instances be more easily or accurately controlled than methodsrelying solely on spraying of polymers toward a core. This may conferthe further advantage that medical devices may be made with smallerdimensions, such as smaller diameters than hitherto. The presentinvention allows for the manufacture of balloons with relatively lowdiameters which, in comparison to devices with larger diameters,facilitate introduction into the vascular system of a living being andreduce side-effects which may occur as a consequence of the introductionof the balloon. The spinning of nanofibers allows for the manufacture ofintegrated composite devices, in which two or more materials areinterlocked on a molecular scale in small dimensions while maintaining asufficient mechanical stability. Cross-sectional dimensions as small asthe dimension of approximately 2-5 molecules of the spun material may beachieved. The size of the molecules evidently depends from the sourcematerial used, the size of a polyurethane molecule being usually in therange of less than 3000 nanometers.

One applicable way of producing nanofibers is to form the fibers byelectrospinning. It should be understood that the term electrospinningcomprises a process wherein particles are applied onto a base elementwhich is kept at a certain, preferably constant, electric potential,preferably a negative potential. The particles emerge from a sourcewhich is at another, preferably positive potential. The positive andnegative potentials may e.g. be balanced with respect to the potentialof a surrounding environment, i.e. a room in which the process is beingperformed. The potential of the base element with respect to thepotential of the surrounding atmosphere may preferably be between −5 and−30 kV, and the positive potential of the source with respect to thepotential of the surrounding atmosphere may preferably be between +5 and+30 kV, so that the potential difference between source and base elementis between 10 and 60 kV.

The art of producing nanofibers has developed considerably in recentyears. U.S. Pat. No. 6,382,526, which is hereby incorporated byreference, discloses a process and apparatus for the production ofnanofibers, which process and apparatus are useful in the methodaccording to the present invention, and U.S. Pat. No. 6,520,425, whichis hereby incorporated by reference, discloses a nozzle for formingnanofibers. It should be understood that the processes and apparatusesof the aforementioned US patents may be applicable in the methodaccording to the present invention, but that the scope of protection isnot restricted to those processes and apparatuses. The fibers may e.g.be spun onto the balloon, as the balloon is continuously rotated, i.e.to form peripherally and/or longitudinally extending strands ofnanofibers in the outer surface layer of the balloon.

The balloon may be produced by the present invention may define aplurality of sections along its length. For example, the sections mayhave different properties, such as different hardness. Such differentproperties may be arrived at by employing different fiber-formingmaterials for different sections and/or by changing productionparameters, such as voltage of electrodes in an electrospinning process,distance between high-voltage and low-voltage electrodes, rotationalspeed of the device (or of a core wire around which the device ismanufactured), electrical field intensity, corona discharge initiationvoltage or corona discharge current.

The body part of the balloon may for example be made of a polyamidematerial, such as Nylon-12 or Ticoflex™ or a combination thereof. Forexample, the balloon body may be made from Nylon-12 provided with acoating a Ticoflex™, onto which the outer surface layer is formed byelectrospun nanofibers. Alternatively, Ticoflex™ may be used directly asa polymer used for forming the nanofibers.

It has also been found that balloons produced by preferred embodimentsof the method according to the invention have a low surface friction. Inembodiments of the invention, a low surface friction may be achieved byapplying a hygroscopic material as a fiber forming material for thefiber forming process, e.g. the electrospinning process. Accordingly,once introduced into the vascular system, the hygroscopic materialabsorbs bodily fluid, resulting in a hydrophilic low-friction surface. Ahygroscopic surface may for example be achieved with a polyurethane or apolyacrylic acid material.

Preferably, the outer surface layer of the balloon may constitute areservoir to drugs. The nanofiber portions thereof constitute reservoirsfor holding drugs or constitute a matrix polymer source where the drugis either blocked into the molecule chain or adheres to or surrounds themolecule chain. The balloons disclosed herein may carry any appropriatedrug, including but not limited to nitric oxide compositions, heparinand chemotherapeutical agents.

The outer surface layer of the expandable balloon may be made fromnanofibres which incorporate at least one pharmaceutically activesubstance. The fibres may form a polymer matrix of one or more polymers.It should be understood that the “outer surface layer made from fibres”,i.e. the polymer matrix, needs not to be the outermost layer of theballoon, for example a layer of a hydrophilic polymer (e.g. polyacrylicacids (and copolymers), polyethylene oxides, poly(N-vinyl lactams suchas polyvinyl pyrrolidone, etc.) may be provided as a coating on theouter surface layer (polymer matrix). Alternatively, a barrier layer maybe provided as coating on the outer surface layer (polymer matrix) inorder to ensure that contact between the polymer matrix and blood isdelayed until the expandable balloon is in place. The barrier layer mayeither be formed of a biodegradable polymer which dissolves ordisintegrates, or the barrier layer may be disintegrate upon inflationof the balloon.

By the term “polymer matrix” is meant the three-dimensional structureformed by the electrospun fibers. The polymer matrix may becharacterized by a very high accessible surface area which allows swiftliberation of the pharmaceutically active substance(s). The polymer ofthe polymer matrix may be prepared from various polymer-based materialsand composite matrixes thereof, including polymer solutions and polymermelts. Applicable polymers are, e.g., polyamides including nylon,polyurethanes, fluoropolymers, polyolefins, polyimides, polyimines,(meth)acrylic polymers, and polyesters, as well as suitable co-polymers.Further, carbon may be used as a fiber-forming material.

The polymer matrix is formed of one or more polymers and may—in additionto the pharmaceutically active substance(s)—incorporate or compriseother ingredients such as salts, buffer components, microparticles, etc.

By the term “incorporates at least one pharmaceutically activesubstance” is meant that the pharmaceutically active substance(s) is/areeither present as discrete molecules within the polymer matrix or is/arebound to the polymer(s) of the matrix either by covalent bonds or byionic interactions. In the latter of the two instances, thepharmaceutically active substance(s) typically needs to be liberatedfrom the polymer molecules before the biological effect can enter intoeffect. Liberation will often take place upon contact with physiologicalfluids (e.g. blood) by hydrolysis, ion-exchange, etc.

In one preferred embodiment, the pharmaceutically active substance iscovalently bound to polymer molecules.

The pharmaceutically active substance may be mixed into a liquidsubstance from which the outer surface layer is manufactured.

In one interesting embodiment, the pharmaceutically active substance isa nitric oxide donor. For certain medical treatments, it is desired thatnitric oxide is released into the body tissue in the gas phaseimmediately upon placement of the balloon at the treatment site, orwithin 5 minutes at most from its placement. As nitric oxide is releasedin the gas phase, it may be achieved that no or only few residues of theNO donor are deposited in the tissue.

In preferred embodiments of the present invention, NONO'ates are appliedas nitric oxide donors. NONO'ates break down into the parent amine andNO gas in an acid catalyzed manner, according to the below figure, cf.U.S. Pat. No. 6,147,068, Larry K. Keefer: Methods Enzymol, (1996) 268,281-293, and Naunyn-Schmeideberg's Arch Pharmacol (1998) 358, 113-122.

In this embodiment, NO is released within the polymer matrix formed e.g.by spinning, such as electrospinning. As the matrix is porous, water mayenter into the matrix. The NO molecule can be transported out of thematrix and into the tissue in a number of ways and combinations hereof.In the following some scenarios are described: NO becomes dissolved inwater within the matrix and transported out of the matrix by diffusionor by water flow; NO diffuse out of the matrix in gas form and becomesdissolved in water outside the matrix; NO diffuses from water into thetissue; NO diffuses all the way from the matrix in gas form into thetissue.

As illustrated in the above figure, the rate of NO liberation highlydepends on the pH of the media. Thus, by addition of various amounts ofan acid to the matrix, the rate of NO liberation can be controlled. Asan example, the half-live of NO liberation at pH=5.0 is approximately 20minutes whereas at pH=7.4 the half-live is approximately 10 hours. As anexample, Ascorbic Acid can be used as an acidic agent for enhancingrelease of NO.

Various nitric oxide (NO) donor compounds and polymeric compositionscapable of releasing nitric oxide have also been proposed in the priorart, e.g. U.S. Pat. No. 5,691,423, U.S. Pat. No. 5,962,520, U.S. Pat.No. 5,958,427, U.S. Pat. No. 6,147,068, and U.S. Pat. No. 6,737,447 B1(corresponding to EP 1220694 B1), all of which are incorporated hereinby reference.

In preferred embodiments, the nanofibers are made from polymers whichhave nitric oxide donors (e.g. a diazeniumdiolate moiety) covalentlybound thereto.

Polyimines represent a diverse group of polymer which may havediazeniumdiolate moieties covalently bound thereto. Polyimines includepoly(alkylenimines) such as poly(ethylenimines). For example, thepolymer may be a linear poly(ethylenimine) diazeniumdiolate (NONO-PEI)as disclosed in U.S. Pat. No. 6,737,447 which is hereby incorporated byreference. The loading of the nitric oxide donor onto the linearpoly(ethylenimine) (PEI) can be varied so that 5-80%, e.g. 10-50%, suchas 33%, of the amine groups of the PEI carry a diazeniumdiolate moiety.Depending on the applied conditions, the linear NONO-PEI can liberatevarious fractions of the total amount of releasable nitric oxide.

Polyamines with diazeniumdiolate moieties (in particularpoly(ethylenimine) diazenium-diolate) may advantageously be used as apolymer for the nanofiber-forming process by e.g. spinning such aselectrospinning because such polymers typically have a suitablehydrophilicity and because the load of diazeniumdiolate moieties (andthereby the load of latent NO molecules) can be varied over a broadrange, cf. the above example for NONO-PEI.

In another embodiment, the pharmaceutically active substance(s) is/arepresent within the polymer matrix as discrete molecules.

Within this embodiment, it the pharmaceutically active substance(s) maybe contained in microparticles, such as microspheres and microcapsules.Such microparticles are in particular useful in the treatment of cancer.The microparticles may be biodegradable and may be made from abiodegradable polymer such as a polysaccharide, a polyamino acid, apoly(phosphorester) biodegradable polymer, a polymers or copolymers ofglycolic acid and lactic acid, a poly(dioxanone), a poly(trimethylenecarbonate)copolymer, or a poly(α-caprolactone) homopolymer or copolymer.

Alternatively, the microparticles may be non-biodegradable, such asamorphous silica, carbon, a ceramic material, a metal, or anon-biodegradable polymer.

The microparticles may be in the form of microspheres that encapsulatethe pharmaceutically active substance, such as the chemotherapeuticagent. The release of the pharmaceutically active substance preferablycommences after the administration.

The encapsulating microspheres may be rendered leaky for thepharmaceutically active substance by means of an electromagnetic orultrasound shock wave.

In order to facilitate passage of the balloon to the treatment sitealong an often tortuous path, a hydrophilic layer is preferably appliedto the outer surface layer. The hydrophilic layer may be provided as aseparate layer of material. Alternatively, the outer surface layer mayitself exhibit hydrophilic properties.

The outer surface layer may advantageously include an acidic agent, suchas lactic acid or vitamin C, which acts as a catalyst for releasing thepharmaceutically active substance, e.g. nitric oxide. The acidic agentis capable of changing the ph-value at the treatment site, the releaserate of nitric oxide at the treatment site varying as a function of thelocal ph-value. Thus, the presence of vitamin C may boost the nitricoxide release, i.e. provide a shock-like release of nitric oxide.

In general, the release of nitric oxide is described in Prevention ofintimal hyperplasia after angioplasty and/or stent insertion. Or, How tomend a broken heart by Jan Harnek M D, Heart Radiology, University ofLund, Sweden, 2003.

The pharmaceutically active substance may be provided in the form ofbiodegradable beadings distributed between the nanofibers, the beadingsbeing capable of releasing the pharmaceutically active substance and, inthe case of biodegradable beadings, to degrade following release. Suchbeadings, which are described in more detail in WO 2005/018600 which ishereby incorporated by reference in its entirety, may penetrate into thetissue at the treatment site and release the pharmaceutically activesubstance there. Alternatively, they may be of a size which is so smallthat they may be transported away, e.g. with the flow of blood, awayfrom the treatment site.

The outer surface layer may be formed on a separate flexible tube or“sock” which is slipped over the balloon. Accordingly, various flexibletubes having various properties or incorporating variouspharmaceutically active substances may be inexpensively manufactured andslipped over traditional, mass manufactured balloons. The flexible tubemay be formed by providing a core element, such as a mandrel, onto whichthe nanofibers are deposited by e.g. spinning, such as electrospinning,as the mandrel is continuously rotated.

In an unexpanded state of the balloon, the flexible tube may be foldedaround, so that the flexible tube, when seen in cross-section, defines aspoke-and-hub-formation.

In order to improve adhering of the outer layer to the balloon body, theballoon body may be covered by an intermediate polymer layer, such as aTicoflex™ layer, before it is being coated. For example, theintermediate layer may be formed by dip-coating the balloon body. Theintermediate layer may alternatively be formed by a polyurethan or bythe polymer which is also used for the outer surface coating, e.g. alinear poly(ethylenimine) diazeniumdiolate as disclosed in U.S. Pat. No.6,737,447 B1. Dip coating is known per se. For example, dip coating isused in the rubber industry for the manufacture of latex products, andco-extrusion is e.g. applied in the manufacture of fibre-optics cables.Braiding may be employed as an alternative to dip-coating for achievinga roughened or textured surface.

In a further aspect, the invention provides a method of treating celldisorders, such as inflammation, proliferation or cancer, in tubularstructures of a living being, comprising the steps of:

-   -   placing a balloon as discussed above at a treatment site within        the tubular structures;    -   expanding the balloon at the treatment site;    -   releasing the pharmaceutically active substance at the treatment        site.

The step of releasing the pharmaceutically active substance may becontrolled by the presence of a ph-controlling substance incorporated inthe outer surface layer, e.g. an acidic agent, such as C vitamin(ascorbic acid) or lactic acid.

Prior to the step of placing the balloon, an unexpanded stent may beplaced on the balloon, which stent may be placed at the treatment sitealong with the balloon. In such an embodiment, the stent is subsequentlyexpanded at the treatment site as the balloon is being expanded, andfinally the balloon is deflated and removed from the tubular structurewhile the stent is left at the treatment site. This confers theadvantage that the delivery of the pharmaceutically active substancedoes not commence fully until inflation of the balloon, and thatdelivery is substantially interrupted as soon as the balloon is deflatedand removed, so that the time of delivery may be accurately controlled.Moreover, the amount of drug which is lost when the stent is conveyedthrough tubular structures of the living being to the treatment site maybe reduced.

In a yet further aspect, the invention also provides a kit comprising acoated balloon as described above, a stent and optionally a guide wirefor guiding the stent to the treatment site.

BRIEF DESCRIPTION OF THE DRAWINGS

Embodiments of the invention will now be further described withreference to the drawing, in which:

FIGS. 1-6 are step-by-step illustrations of a preferred embodiment of amethod for producing a medical tubing, e.g. a tubular member for anembodiment of a balloon according to the present invention;

FIG. 7 shows an embodiment of an angioplasty balloon catheter comprisinga balloon according to the present invention;

FIGS. 8 and 9 illustrate folding of a balloon.

DETAILED DESCRIPTION OF THE DRAWING

In the embodiment of FIGS. 1-6, the nanofibers are spun onto an outersurface of a core member. The core member comprises a core wire (ormandrel) 100, a layer 102 of PTFE applied to an outer surface of thecore wire, a coating 104 of a thermoplastic material applied to an outersurface of the PTFE layer 102, and at least one reinforcing wire 106applied to an outer surface of the thermoplastic coating, with thefilaments of nanofibers being provided as an outer layer 108, i.e.enclosing the reinforcing wire and the thermoplastic coating. Thenanofibers may e.g. be produced as devised in U.S. Pat. No. 6,382,526 orU.S. Pat. No. 6,520,425 and subsequently spun onto the intended targetobject, e.g. during rotation thereof. The nanofibers may likewise beformed by electrospinning, also during continuous rotation of the targetobject. A hydrophilic layer 110 is optionally applied to an outersurface of the device, cf. FIG. 6.

The diameter of the guide wire may be at least 0.1 mm, such as in therange of 0.1 to 1.0 mm or larger. The thermoplastic coating, which ispreferably a coating of polyurethane (PU), preferably has a thickness of5 μm to about 0.05 mm, preferably 0.01 mm±20%. The reinforcing wire(s)preferably has/have a diameter of 5 μm to about 0.05 mm, preferably 0.01mm±20%.

As described above, a layer of PTFE 102 may be applied to an outersurface of the core member 100. At least a portion of the surface of thelayer of PTFE, such as the portion onto which the nanofibers and/or thethermoplastic coating are to be applied, may be modified for improvedbonding of material to the outer surface of the PTFE layer. Preferably,such modifying comprises etching, which may for example result in aprimed PTFE surface for covalent bonding or gluing. Etching may beachieved by applying a flux acid or hydroflouric acid to a surface ofthe PTFE layer. The layer of PTFE may be provided as a hose which isslipped over and co-extends with the core wire.

A coating of a thermoplastic material 104, such as polyurethan (PU), maybe provided to an outer surface of the core member 100, i.e. to an outersurface of the PTFE layer 102 in case such a layer has been provided.Following the step of providing the layer of PTFE 102 and/or the step ofproviding the thermoplastic coating 104, one or more reinforcing wires106 may be applied to an outer surface of the core member 100, i.e., ina preferred embodiment, to an outer surface of the polyurethane coating104. The reinforcing wire(s) may consist of one or wires made from steelor/and wires made from yarn, such as carbon filament, which may beapplied by winding. Alternatively, the reinforcing wire may be appliedby spinning of nanofibers, such as by electrospinning as describedabove. The reinforcing wire may be formed from carbon or polymer,including polymer solutions and polymer melts. Applicable polymers are:nylon, fluoropolymers, polyolefins, polyimides, and polyesters.

While forming the tubular member, or at least while forming that portionof the tubular member which is formed by nanofibers, e.g. byelectrospinning, the core member 100 is preferably rotated, so as toevenly distribute the nanofibers around the outer surface of the coremember.

In a preferred embodiment of the invention, nanofibers 108 are appliedto the outer surface of the core member at this stage, that ispreferably to the outer surface of the thermoplastic coating 104 whichis optionally reinforced by the reinforcing wire(s).

A solvent, such as tetrahydroforane (THF) or isopropanol alcohol (IPA),may subsequently be applied to an outer surface of the core member, theouter surface being defined by the nanofiber portion (or layer) 108 ofthe device. The thermoplastic coating 104 thereby at least partiallydissolves in the solvent, so as to bond the reinforcing wire(s) 106thereto. The reinforcing wire(s) 106 thereby become(s) embedded in thethermoplastic coating 104. It has been found that the step of providingthe solvent results in a highly dense surface with a low surfacefriction, which is believed to be due to crumpling or shrinking ofstretched molecules of nanofibers once the solvent is applied.

The core wire 100 (or mandrel) is removed from the device following thestep of applying the solvent or prior to the step of applying solventbut subsequent to the step of applying the filament of nanofibers 108.

The resulting tubular member may be used as a flexible tube or sockwhich may be slipped over a balloon.

Alternatively, nanofibers may be formed directly onto the balloon byelectrospinning, the balloon being optionally coated, e.g. dipcoated, orbraided as discussed above to enhance adhering of the nanofibers to itssurface.

FIG. 7 shows different embodiments of an angioplasty balloon cathetercomprising a balloon in accordance with the present invention. In theupper drawing of FIG. 7 there is shown an inflated balloon 118 whichcomprises an outer surface layer 120 made from electrospun nanofibers.The balloon is carried by a guidewire 122.

The middle drawing of FIG. 7 shows a non-inflated balloon 124 over whichthere is slipped a tube or “sock” 126 made from electrospun nanofibers.In the lower drawing of FIG. 7, the dashed lines show the contour of theballoon 124 and the sock 126 when the balloon is inflated.

FIGS. 8 and 9 are schematic illustrations of an unexpanded state of aballoon, wherein a flexible tube is folded, so that the flexible tube,when seen in cross-section, defines a spoke-and-hub-formation.

1. An expandable balloon for use in angioplasty procedures, comprising aballoon having an outer surface layer, the outer surface layer beingmade from nanofibers and incorporating at least one pharmaceuticallyactive substance.
 2. A balloon according to claim 1, further comprisingan intermediate layer formed between the balloon and the outer surfacelayer, the intermediate layer being formed by dip-coating.
 3. A balloonaccording to claim 1, wherein the outer surface layer is formed on aseparate flexible tube and the outer surface layer is slipped over theballoon.
 4. A balloon according to claim 3, wherein the flexible tube isfolded, so that the flexible tube, when seen in cross-section, defines aspoke-and-hub-formation.
 5. A balloon according to claim 1, wherein thepharmaceutically active substance comprises nitric oxide, and whereinthe outer surface layer optionally further includes an acidic agent. 6.A balloon according to claim 1, wherein the outer surface layer isessentially made from a polymer matrix, which contains molecules capableof releasing the at least one pharmaceutically active substance.
 7. Aballoon according to claim 6, wherein the outer surface layer isessentially made from a polymeric linear poly(ethylenimine)diazeniumdiolate.
 8. A balloon according to claim 1, wherein thepharmaceutically active substance is provided in the form ofbiodegradable beadings distributed between the nanofibers.
 9. A balloonaccording to claim 1, wherein the outer surface layer is formed fromspun nanofibers, such as electrospun nanofibers.
 10. A kit comprising astent and a coated balloon according to claim 1 for expanding the stent.11. A kit according to claim 10, further comprising a guide wire forguiding the stent to a treatment site in tubular structures of a livingbeing.
 12. A kit according to claim 11, wherein the guide wire isprovided with a coating.
 13. A method of producing a balloon for use inangioplasty, the method comprising the step of forming an outer surfacelayer for the balloon by nanofibers, the outer surface layer containingat least one pharmaceutically active substance.
 14. A method accordingto claim 13, wherein the outer surface layer is formed by spinning, suchas by electrospinning.
 15. A method according to claim 14, wherein theouter surface layer is applied in the unexpanded state of the balloon.16. A method according to claim 13, further comprising, prior to thestep of forming the outer surface layer, a step of dip-coating theballoon to form an intermediate layer.
 17. A method according to claim13, comprising: forming the outer surface layer on a separate flexibletube; slipping the flexible tube over the balloon.
 18. A methodaccording to claim 17, wherein the step of forming the outer surfacelayer on the flexible tube comprises: providing at least one coremember; forming the flexible tube with the outer surface layer byelectrospinning the nanofibers onto an outer surface of the core member.19. A method according to claim 17 or 18, further comprising, subsequentto the step of slipping the flexible tube over the balloon, folding theflexible tube, so that the flexible tube, when seen in cross-section,defines a spoke-and-hub-formation.
 20. A method according to claim 13,wherein the pharmaceutically active substance comprises nitric oxide.21. A method according to claim 20, wherein the outer surface layerfurther comprises an acidic agent.
 22. A method according to claim 13,wherein the outer surface layer is essentially made from a polymermatrix, which contains molecules capable of releasing the at least onepharmaceutically active substance.
 23. A method according to claim 22,wherein the outer surface layer is essentially made from a polymericlinear poly(ethylenimine) diazeniumdiolate.
 24. Use of an acidic agentas catalyst for the release of nitric oxide in a balloon according toclaim
 1. 25. A method of treating cell disorders in tubular structuresof a living being, comprising the steps of: placing a balloon accordingto claim 1 at a treatment site within the tubular structures; expandingthe balloon at the treatment site. releasing the pharmaceutically activesubstance at the treatment site.
 26. A method according to claim 25,wherein the step of releasing is controlled by the presence of aph-controlling substance contained in the outer surface layer.
 27. Amethod according to claim 24, further comprising, prior to the step ofplacing the balloon, placing an unexpanded stent on the balloon; andplacing the stent at the treatment site along with the balloon; andsubsequently expanding the stent at the treatment site as the balloon isbeing expanded; and subsequently deflating the balloon and removing itfrom the tubular structure while the stent is left at the treatmentsite.